Cephalosporin compositions

ABSTRACT

Silylated cephalosporin compositions containing (a) silyated cephalosporin nucleus compound, (b) a silylamide, and (c) an anhydrous solvent for components (a) and (b), which solvent does not contain Zerwitinoff hydrogen.

United States Patent Jackson CEPHALOSPORIN COMPOSITIONS Inventor: Billy C. Jackson, Indianapolis, lnd.

Assignee: Eli Lilly and Company, Indianapolis, Ind.

Filed: Aug. 19, 1970 Appl. No.: 65,237

Related U.S. Application Data Continuation-impart of Ser. No. 754,992, Aug. 23, 1968, abandoned.

U.S. Cl. ..252/ 182, 260/243 C Int. Cl. ..C07d 99/24 Field of Search ..260/243 C; 252/ l 82 [451 June 20, 1972 Primary Examiner-Mon D. Rosdol Assistant Examiner-Irwin Gluck Attomey-Everet F. Smith and John T. Reynolds [57] ABSTRACT Silylated cephalosporin compositions containing (a) silyated cephalosporin nucleus compound, (b) a silylamide, and (c) an anhydrous solvent for components (a) and (b), which solvent does not contain Zerwitinofi hydrogen.

5 Claims, No Drawings CROSS REFERENCE This application is a continuation-in-part of application Ser. No. 754,992, filed Aug. 23, 1968 and now abandoned.

BACKGROUND OF THE INVENTION l Field of Invention and Objects of the Invention This invention relates to cephalosporin compound technology. It is particularly concerned with providing certain improvements in the processes that are used in manufacturing cephalosporin antibiotic compounds where acylation of a cephalosporin nucleus is the route selected.

Cephalothin is now a well-known and widely used antibiotic. It is sold commercially in the form of the sodium salt. This antibiotic is generally made by acylation of the so-called ce halosporanic acid nucleus, 7-aminocephalosporanic acid, commonly abbreviated 7-ACA, with thiophene-Z-acetic acid or an activated acylating form of that acid. .Cephaloridine, another potent cephalosporin antibiotic, is generally prepared by reacting pyridine with cephalothin, although it also can be prepared by acylating the cephalosporin C pyridine) nucleus, 7-amino-3-( N-pyridino-methyl )-A -cephem-4-carboxylic acid with thiophene -2-acetic acid or an activated form thereof as indicated above. The relatively new orally active cephalosporin antibiotics cephaloglycin and cephalexin are fonned by acylating the cephalosporin nuclei 7-ACA and 7aminodesacetoxycephalosporanic acid (7-ADCA), respectively, with a mixed anhydride of an N-protected form of phenylglycine.

' An object is to provide certain new silylated cephalosporin compositions which are useful as intermediates in the production of cephalosporin antibiotics.

2. Description of the Prior Art In British Pat. No. 1,073,530 there is disclosed the use of certain silyl chlorides or amines in the process of making certain cephalosporins. However, that patent in no way discloses any specific cephalosporins or the use of the herein described silylated amide compounds. Furthermore, the silyl amide method of this invention offers several advantages over the method of the British patent. By the method of this invention, the silylation of the cephalosporin nucleus such as 7-ACA or 7-ADCA may be performed at room temperature or below, thus avoiding thermal degradation of the cephalosporin nucleus. Also, excess silylating agent does not have to be removed from the silylated cephalosporin nucleus prior to the acylation step, whereas this removal step is a prerequisite where silyl amine or silazanes are used as silylated agents. By the use of this invention no base is liberated or employed in the silylation reaction, thus avoiding the possible isomerization of the delta-3-double bond in the cephalosporin nucleus end product. Also. by this process it is not necessary to provide for the elimination of by-product hydrogen chloride generated when silyl chlorides are used, following the above British patent procedure.

SUMMARY OF THE INVENTION This invention provides new compositions comprising (a) a silylated cephalosporin nucleus compound, (b) a mono or his silylamide, and (c) an anhydrous solvent for components (a) and (b), which solvent molecules do not contain Zerewitinoff hydrogen. These new compositions are useful in processes for preparing cephalosporin antibiotic' compounds from the respective cephalosporin nuclei compounds. Of particular in terest in the use of silylated 7-aminocephalosporanic acid compositions of this invention in a manufacturing process for preparing cephaloglycin which is the generic name for 7-[D-2 '-amino-2-phenylacetamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid. However, the process can also be used to prepare a variety of cephalosporin antibiotic compounds from the respective silylated cephalosporin nucleus compounds.

DETAILED DESCRIPTION OF THE INVENTION Specific starting materials, intermediates. and products of the process of this invention are named, for convenience, by use of .the cephem nOmenclature system which has been adapted to cephalosporin compounds from an analogous nomenclature system, based on penam' for naming specific penicillin compounds. Penam nomenclature for the penicillins is described by Sheehan, Henery-Logan, and Johnson in the Journal of American Chemical Society (JACS), 75, 3292, footnote 2, (I953), and has been adapted to the cephalosporins by Morin et al. in JACS, 84, 3400 (1962). In accordance with these systems of nomenclature, "mum" and cepham refer respectively to the following saturated ring systems Penam Cepham Cephem refers to the cepham ring structure containing a double bond, the position of which is indicated by the prefix A" with an integer superscript denoting the lowest numbered carbon atom to which the double bond connected, or by the word delta with the same number relationship. Occasionally, a number immediately preceeding the word cephem" is used by itself to indicate the position of the double bond in the cephem structure. Thus, 7- aminocephalosporanic acid (7-ACA) can be named 7-amino- 3-acetoxymethyl-66 -cephem-4-carboxylic acid, while a corresponding silylated product of the process of this invention can be named triethylsilyl 7-(N-triethylsilyl)amino-3-acetoxymethyl-A"-cephem-4-carboxylate. Similarly, by this system 7- ADCA can be named 7-amin0-3-methyl-A -cephem-4-carboxylic acid.

The preferred cephalosporin nucleus compounds are defined herein as being compounds of the formula COOH wherein R" is hydrogen, or a nucleophilic group useful in cephalosporin antibiotic compounds, such as a C, to C -alkanoyloxy, a C to C -alkylX--, or the like. More specifically, we prefer to work with cephalosporin nucleus compounds were R" is hydrogen, acetoxy, CH;,O, or CH S- so that the respective cephalosporin nuclei compounds are useful in making highly potent known cephalosporin antibiotics. When R" is hydrogen the cephalosporin nucleus compound is 7-aminodesacetoxycephalosporanic acid 7-AD- CA), also named 7-amino-3-methyl-3-cephem-4-carboxylic acid. When R" is acetoxy the cephalosporin nucleus compound is 7-aminocephalosporanic acid (7-ACA). Examples of other useful cephalosporin nucleus compounds for making the compositions of this invention include 7-amino-3- methylthiomethyl-3-cephem-4-carboxylic acid and others disclosed in Belgian Pat. No. 734,532, published Dec. 16, I969, and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid, and others disclosed in Belgian Pat. No. 7l9,7l0 published Feb. 20, 1969.

This invention provides compositions comprising (a) the silylated cephalosporin nucleus compounds as described herein, (b) at least one of the monoor bis-silylamide compounds of fon'nulas I, II, III, IV, and V described herein, and (c) an anhydrous solvent for components (a) and (b) which solvent molecules do not contain Zerewitinoff hydrogen. Component (b) can be any of the disclosed silylamides. The excess monoor bis-silylamide reactant used in the formation of the silylated cephalosporin nucleus compound (a) can be used to satisfy component (b). Such excess silylamide serves to take up any water or alcohol introduced into the composition by atmospheric conditions or chemical reactions. These compositions are useful as such for reacting with the appropriate acylating agent to form cephalosporin antibiotics. For example, these compositions can be reacted with a mixed anhydride of an N-protected phenylglycine as described above to form cephaloglycin (from the silylated 7-ACA compositions) and cephalexin (from the silylated 7-ADCA compositions), respectively, which cephalosporins are known antibiotics.

in preparing the compositions of this invention, a reactive form of the cephalosporin nucleus compound, e.g., in zwitterionic or soluble salt form is reacted with a silicon compound having a fonnula selected from the group consisting of each of R,, R and R is selected from the group consisting of hydrogen and hydrocarbon radicals free of aliphatic unsaturation and having from one to eight carbon atoms with not more than two of any R, R and R bonded to the same silicon atom being hydrogen;

R is hydrogen or a hydrocarbon radical which is free of aliphatic unsaturation and contains from one to eight carbon atoms;

Y is an alkylene group having from three to 18 carbon atoms with a chain of at least three but no more than five carbon atoms extending between the nitrogen and the carbonyl group to which Y is bonded;

each of R, R and R taken separately, is hydrogen or a hydrocarbon group free of aliphatic unsaturation containing from one to eight carbon atoms, and R and R taken together with the nitrogen to which they are bonded, complete a heterocyclic ring containing from five to six ring forming atoms, one of which can be oxygen para to the nitrogen, and from four to five ring forming carbon atoms with the proviso that R and R together contain not more than 18 carbon atoms and that if R is an alkyl with a tertiary carbon bonded to the nitrogen then R is hydrogen;

R and R taken together with the nitrogens to which they are bonded and the carbonyl group complete a heterocyclic ring containing from five to six ring forming atoms and from two to three methylene ring forming carbon atoms;

R" is a hydrocarbon group free of aliphatic unsaturation and containing from one to eight carbon atoms; and

R is either hydrogen or a hydrocarbon group free of aliphatic unsaturation and containing from one to eight carbon atoms, in a substantially anhydrous, aprotic liquid solvent, at a temperature of from about -50 C. to about 50 C. to form a compound ofthe formula wherein R, R and R are as defined above and R is hydrogen or the group wherein R,, R and R are as defined above, and R is hydrogen, C, to C -alkanoyloxy, or a C to C -alkylX where X is oxygen or sulfur.

The organic silicon compounds of the class represented by the formulas l and II are defined in detail in U.S. Pat. No. 2,876,234 issued Mar. 3, 1959. These are monosilylated amides but include both the acyclic and cyclic types. The silylated urea amide compounds (Ill) and the silylated urethane or carbamate compounds (lV) can be prepared as described in U.S. Pat. No. 2,876,209. Bis-silyl compounds of formula V are well-known compounds and have been described in publications such as the one found in the Journal of the American Chemical Society, Volume 88, page 3390.

Examples of the intermediate compounds which can be produced in the process of this invention and the reactants from which they can be prepared include:

Triethylsilyl 3-methyl-7(N-triethylsilylamino)-A-cephem- 4-carboxylate from 7-ADCA and N,0-bis(triethylsilyl)-acetamide;

Trihexylsilyl 3-acetoxymethyl-7-( N-trihexylsilylamino) -A cephem-4-carboxylate from 7-ACA and l-(trihexylsilyl)-2- piperidinone;

Triphenylsilyl 3-methyl-7-(N-triphenylsilylamino)-A cephem-4-carboxylate from 7-ADCA and l-(triphenylsilyl )-2- pyrrolidinone;

Tribenzylsilyl 3-acetoxymethyl-7-(N-tribenzylsilylamino )-A -cephem-4-carboxylate from 7-ACA and N-tribenzylsilyl methyl carbamate;

Dimethyl( phenyl )silyl 3-methyl-7-( N-dimethylphenylsilylamino)-A -cephem-4-carboxylate from 7-ADCA and dimethyl-( phenyl)silylurea, and the like.

Examples of solvents (c) which are free of Zerwitinoff hydrogen include nitn'les, esters, ethers, halogenated alkanes and hydrocarbons, among others. Specific examples include the alkanonitriles having from two to six carbon atoms such as acetonitrile, hexanonitrile, and alkyl alkanoate esters having from four to 10 carbon atoms such as ethyl acetate, propyl acetate, amyl acetate, propyl hexanoate, cyclic and linear ether solvents such as tetrahydrofuran, dioxane, ethyl ether, diphenyl ether, and the like, halogenated alkanes including methylene chloride, chloroform carbon tetrachloride, and hydrocarbon solvents such as hexane, heptane, benzene, toluene, toluene, and xylene, as well as alkanones such as acetone, methyl ethyl keptone, and mixtures of such solvents.

The 7-amino group of the silylated cephalosporin nucleus compound such as the 7-ACA or 7-ADCA intermediates can be reacted with an acylating agent by procedures known to date, for example as described in U.S. Pat. No. 3,382,241. Preferred acylating agents are those which are known to contribute to the making of a cephalosporin compound having optimum antibiotic activity while having other desired properties as well. Such other properties include good water solubility, ease of purification, good absorbability when administered by the oral route, or low degree of pain upon injection and the like, depending upon the intended mode of administration. Examples of such acylating agents are 2-(2-thienyl)acetyl chloride or bromide, and mixed anhydride or activated ester forms of an N-protected phenylglycine such as the methyl N- (tert-butoxycarbonyloxy),phenylglycine mixed carbonic anhydride, isobutyl N-(benzyloxycarbonyloxy)phenylglycine mixed carbonic anhydride, ethyl N-(2,2,2-trichloroethoxycarbonyloxy)-phenylglycine mixed carbonic anhydride and cyanomethyl N-(tert-butoxycarbonyloxy)phenylglycinate ester and the like.

These silylated cephalosporin compositions can be used in processes for preparing a variety of known cephalosporin antibiotlcs, such as cephalothin, cephaloridine, cephaloglycin, and cephalexin. For example, these silylated cephalosporin intermediates derived from 7-ACA may be directly acylated with thiophene-2-acetyl chloride. Acylation of the above silylated product where R is acetoxy with an N-protected activated form of phenylglycine, followed by treatment with methanol, and pH adjustment to the isoelectric point yields cephaloglycin.

Cephalothin may be recovered as the alkali metal salt, e.g., the sodium or potassium salt by addition of sodium or potassium acetate. When cephaloglycin or cephalexin or similar amino group containing cephalosporin antibiotics are being prepared the N-protecting group must be removed from the amino-acid moiety of the cephalosporin. For this purpose water, acid, or mixtures thereof are added to the cephalosporin containing mixture simultaneously with or soon after the alcohol addition. The resulting amino-group containing cephalosporin product can be separated from the reaction mixture by adjusting the pH of the mixture of the isoelectric point of the cephalosporin at which pH the cephalosporin separates from the mixture from which it can be recovered by conventional chemical methods.

The invention is further exemplified by the following detailed examples, which are not intended as being limited to the scope of the invention.

EXAMPLE 1 A 10.0 g portion of 7-aminocephalosporanic acid, and 17.6 ml of N-, O-bis-trimethylsilylacetamide, and 100 ml of dry acetonitrile were mixed and stirred at room temperature until trimethylsilyl 7-(N-trimethylsilylamino)-3-acetoxymethyl-A cephem-4-carboxylate was formed. In a separate operation 10.0 g of the N-methyl acetoacetate-blocked phenylglycine, 100 ml of dry acetonitrile, and 0.04 ml of dimethylbenzyl-amine were mixed and cooled to -l C while stirring and to this mixture there was added 3.1 ml of methyl chloroformate (8 percent excess) in one portion, to form a mixed anhydride of the N-protected phenylglycine. The reaction temperature of this second mixture rose to approximately 3 C. Stirring and cooling of the mixture was continued for an additional 3 to 5 minutes during which time the temperature dropped to l0 C. To this a resulting mixed anhydride solution was added the above trimethylsilyl 7-( N-trimethylsilylamino )-3-acetoxymethyl-A cephem-4-carboxylate solution which had been previously chilled to about l0 C at such a rate as to maintain the temperature at l 0 C to about 5 C. Addition generally required from about 4 to 8 minutes. Following the addition, the reaction mixture was stirred, and the cooling vessel was allowed to warm up. After I hours the temperature was about 3 C. All of the above operations were conducted with precautions taken to exclude atmospheric moisture. In this example a drying tube containing DRlERlTE drying agent was used.

The acylation reaction mixture was then chilled to 0 C and 50 ml of methanol was added. Stirring was continued for 10 minutes after which time the mixture was filtered with the aid of a filter aid (HYFLO-SUPER-CEL). The volume of the filtrate and the methanol washes which followed was adjusted to 350 ml and then 50 ml of deionized water was added. Cephaloglycin as the zwitterion separated afier a few minutes stirring at 0 C. Stirring at 0 C was continued for 2 to 3 hours to insure precipitation of most of the cephaloglycin and then the product was filtered. rinsed with acetonitrile, and vacuum dried at about 40 C. Yield of dry EXAMPLE 2 In an environment protected from atmospheric moisture trimethylsilyl 7-(N-trimethylsilylamino)-3-acetoxymethyl-A cephem-4-carboxylate was first prepared by combining l0.0 grams of 7-ACA in ml of dry acetonitrile with 20 g (86 millimoles) of N-trimethylsilylacetamide which mixture was stirred at room temperature for 60 minutes to insure solution. The trimethylsilyl 7-(N-trimethylsilylamino)-3-acetoxymethyl-A -cephem-4-carboxylate solution was cooled to 5 C and then 5.7 ml of dry triethylamine was added in one portion. Then while stirring the mixture and continuing the cooling, a solution of 7.45 g of 2-(2'-thienyl)acetyl chloride (40.5 millimoles) in 20 ml of dry acetonitrile was added. The rate of addition was slow enough to keep the temperature below 5 C. The addition required about 25 minutes. When the addition was completed, the mixture was stirred at about 0 C for onehalf hour to insure complete reaction. The acylation reaction mixture was allowed to warm to 35 to 40 C for about 20 minutes and then the solution was stripped of solvent, and the residue was taken up in methanol and the insoluble material was filtered off. The resulting methanol solution of the crude cephalothin product was stripped and the residue was taken up in water and ethyl acetate mixture. The pH of the mixture was adjusted to about 6.6 with l N sodium hydroxide. The aqueous phase of the resulting mixture was separated and the organic phase was discarded. The aqueous phase was layered with fresh ethyl acetate and the pH was adjusted to 2.0 with concentrated hydrochloric acid. After additional washes with ethyl acetate to insure collection of most of the cephalothin product in the organic phase, the ethyl acetate phases were dried over magnesium sulfate and stripped to obtain about 13 g. of cephalothin as product of the process.

EXAMPLE 3 In an environment protected from atmospheric moisture, a mixture of 7.2 g (33.8 millimoles) of 7-aminodesacetoxycephalosporanic acid, (7-ADCA) 17.6 ml (73.8 millimoles) of N,O-bis(trimethylsilyl)acetamide, and 100 ml of dry acetonitrile was stirred at room temperature for 2 hours. The resulting trimethylsilylated 7-ADCA was added to the mixed anhydride ybenzylamino)crotonate, sodium salt, 3.] ml of methyl chloroforrnate, in 100 ml acetonitrile, containing 0.04 ml of N,N-dimethyl-N-benzylamine, cooled to 1 0 C. The resulting mixture was stirred for 65 minutes and then 50 ml. of methanol was added, and the mixture was stirred for an additional 10 minutes at about 3 C. The mixture was filtered through a filter aid (HYFLO) and rinsed with acetonitrile. The filtrate and the washes were combined and chilled to 0 C and then 50 ml of water was added. Concentrated hydrochloric acid was added until the pH of the filtrate and washes was 2.0. Triethylamine was added to raise the pH to pH 4.2. The cephalexin which precipitated was filtered, rinsed with acetonitrile, and vacuum dried at about 40 C. There was obtained 10.0 g. of cephalexin.

Alcohols other than methanol such as benzyl alcohol and other lower alkanols having from 2 to 6 carbons, e.g., ethanol,

n-propanol. isopropanol n-butanol, isobutanol, tert-butanol mixed amyl alcohols. hexanol can also be used, but methanol or ethanol is preferred.

EXAMPLE 4 Following the procedure of Example 1, 7-ADCA is reacted with two molar equivalents of N-(triphenylsilyl)ethylcarbamate to form a triphenylsilyl 7-(triphenylsilylamino)-3- methyl-A-cephem-4-carboxylate intermediate. This intermediate is reacted with an N-methyl acetoacetate)-protected a-amino-2-( 2-thienyl) acetyl chloride and the resulting acylated product is treated with methanol and then with aqueous base to form 3-methyl-7-[(a-amino( 2-thienyl)acetamido] -A"-cephem-4-carboxylate acid as the zwitterion, a known antibiotic.

EXAMPLE 5 Following the procedure of Example 3, 7-ADCA is treated with N-(triethylsilyl )urea to form a triethylsilylated 7-ADCA ester. This ester is treated with a mixed anhydride resulting from N-(benzyloxycarbonyl)phenylglicine and methyl chloroformate. The resulting acylated product is treated with methanol and then with aqueous acid to pH 2.0 to remove the protecting groups. Addition of base to the isoelectric point (about pH 4.2) causes cephalexin to preci itate from the reaction mixture.

EXAMPLE 6 Following the procedure of Example 1, 7-ACA is reacted with an excess molar proportion of the lactam resulting from trimethylsilyl chloride and Z-pyrrolidone to form trimethylsilyl 7-( trimethylsilylamino )-3 acetoxymethyl-A -cephem-4-carboxylate ester. This ester is treated with 2-thienyl)acetyl chloride, and then treated with methanol to form cephalothin, which is removed from the reaction mixture by treatment with sodium acetate to form sodium cephalothin.

EXAMPLE 7 To a slurry of 3.6 g 16.9 moles) of 7-ADCA in 30 ml ofdry acetonitrile was added 8.8 ml (33.5 moles) of N,O- bis(trimethylsilyl)acetamide (BSA). Upon mixing a slight exotherm was observed and after stirring at room temperature for a period of one-half hour. all of the 7-ADCA had dissolved. Analysis of the resulting solution by nuclear magnetic resonance (NMR) spectroscopy indicated that the product was trimethylsilyl 7-(trimethylsilyl)amino-A -cephem-4-carboxylate in acetonitrile solution. When less BSA was employed under the same conditions, NMR analysis indicated that the reaction product was a mixture of the above bis-silylated cephalosporin together with trimethylsilyl 7-amino-A cephem-4-carboxylate.

Similar results are obtained using N-trimethylsilylacetamide as silylating agent.

EXAMPLE 8 5.0 g. of 7-ACA, 8.8 ml (33.5 millimoles) BSA and 50 ml dry acetonitrile were mixed and stirred at room temperature for a period of two hours during which time the 7-ACA dissolved. NMR analysis of the resulting solution indicated that the product was trimethylsilyl 7-trimethylsilylamino-3- cephem-(ceph-3-em )-4-carboxylate mixed with excess BSA.

in another experiment run similarly except that 6.0 ml BSA were employed. NMR analysis indicated that bis-silylation was not complete and the product contained both the above bis-silylated ester and trimethylsilyl-7-amino-A -cephem-4-carboxylute.

EXAMPLE) A mixture of NH) g. of the cephalosporin nucleus com' pounds 7-amin(iccphulosporunic acid (7-ACA), 20.0 g of N- trimcthylsilylacetamidc (MSA) and 5!) ml. olacetonitrile was stirred for a period of 45 minutes. Protection from atmospher ic moisture was provided for this composition. Separately, a suspension of l 1.0 g. of methyl S-(a-carboxybenzylamino)crotonate, sodium salt, and 50 ml. of acetonitrile was chilled to l5 C and kept in a range of from -l0 C to 40 C 3.4 ml of methyl chloroformate was added followed by 0.03 ml. of N,N-dimethylbenzylamine. Following the amine addition the reaction mixture was stirred for 5 minutes at 10 C or below. When temperatures of about 40 C are used stirring fro about 20 minutes is recommended. To the mixed anhydride solution was then added to the solution of silylated 7-ACA composition (precooled to -l0 C or less) over a period of 5 minutes.

The mixture was then allowed to react for a period of 1 hour allowing the temperature to rise to +5 C. Stirring continued for an additional 0.5 hour at 0 to 5 C. Then 25 ml of methanol was added and the pH of the mixture was adjusted to L5 with concentrated hydrochloric acid. Then 0.5 g of Darco" brand decolorizing carbon was added and the mixture was filtered through a filter aid (Hyflo"). The filtrate was then adjusted to pH 4.5 using triethylamine. The 7-[D-2'-amino-2- phenylacetamido]cephalosporanic acid product (cephaloglycin) crystallized from the mixture. It was stirred at 0 to 5 for 2 hours. Then the product was filtered off, washed with methanol, and acetonitrile and vacuum dried at 40 C. The usual yield by this procedure is l l to l2.5 g of product.

EXAMPLE 10 Following the procedure of Example 9, 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid is silylated with MSA in acetonitrile to form the silylated 7-amino-3-methoxymethyl-3- cephem-4-carboxylic acid ester intermediate composition. This composition is treated as described in Example 9 to form as product, 7-[D-2'-amino-2 -phenylacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid.

EXAMPLE 1 1 Following the procedure of Example 9, 7-amino-3- methylthiomethyl-3-cephem-4-4-carboxylic acid is silylated with MSA in acetonitrile to form the silylated 7-amino-3- methylthiomethyl -3-cephem-4-carboxylic acid ester intermediate composition. This composition is treated as in Example 9 to form as product 7-[D-2'-amino- 2'-phenylacetamido]- 3-methylthiomethyl-3-cephem-4-carboxylic acid.

EXAMPLE 12 Following the procedure of example 9, the cephalosporin nucleus compound, 7-amino-3-methylthiomethyl-3-cephem- 4-carboxylic acid is silylated with MSA in acetonitrile to form the silylated 7-amino-3-methylthiomethyl- 3-cephem-4-carboxylic acid ester intermediate composition. This composition is treated with D-2-tert-butoxycarboxamido-2-(3'-hydroxyphenyl)acetic acid in place of the mixed anhydride to form as acylated product the 7-[D-2-(tert-butoxycarboxamido)-2- phenylacetamido]-3-methylthiomethyl-3-cephem-4-carboxyl ic acid. After methanol addition and acid treatment there is obtained as product 7-[D-2'-amino-2'-(3"-hydroxyphenyl)acetamido]-3-cephem-4-carboxylic acid, an antibiotic effective against a variety of Gram-positive and Gram-negative microorganisms. For example, this compound had a minimum inhibitory concentration (MlC) value of 0.3l/ml in an agar gradient plate test against the organism, Diplococcus pneunwm'ae, compared to an MlC value of 2.5 ag/ml. for cephalexin in the same test.

lclaim:

l. A composition consisting essentially of (a) a compound of the formula s 1w Nll on (:11 on. I (u N A ount" (In!) It wherein each of R, R and R is selected from the group consisting of hydrogen, and a hydrocarbon group free of aliphatic unsaturation and having from one to eight carbon atoms, with not more than two of R, R, and R bonded to the same silicon atom being hydrogen, R is hydrogen or wherein R, R and R are as defined above, and R is hydrogen, or -XCH where X is oxygen or sulfur (b) sufficient monoor bis-silylamide necessary to keep component (a) silylated and to take up water or alcohol introduced into the composition by atmospheric conditions or chemical reaction, said monoor bis-silylamide having a formula selected from the group consisting of each of R, R and R is selected from the group consisting of hydrogen and hydrocarbon radicals free of aliphatic unsaturation and having from one to eight carbon atoms with not more than two of any R, R, and R bonded to the same silicon atom being hydrogen;

R is hydrogen or a hydrocarbon radical which is free of aliphatic unsaturation and contains from one to eight carbon atoms;

Y is an alkylene group having from three to l8 carbon atoms with a chain of at least three but no more than five carbon atoms extending between the nitrogen and the carbonyl group to which Y is bonded;

Each of R", R, and R, taken separately, is hydrogen or a hydrocarbon group free of aliphatic unsaturation containing from one to eight carbon atoms, and R' to R taken together with the nitrogen to which they are bonded, complete a heterocyclic ring containing from five to six ring forming atoms, one of which can be oxygen para to the nitrogen, and from four to six ring forming carbon atoms with the proviso that R and R together contain not more than 18 carbon atoms and that if R is an alkyl with a tertiary carbon bonded to the nitrogen then R is hydrogen;

R and R taken together with the nitrogen to which they are bonded and the carbonyl group complete a heterocyclic ring containing from five to six ring forming atoms and from two to three methylene ring forming carbon atoms;

R is a hydrocarbon group free of aliphatic unsaturation and containing from one to eight carbon atoms; and R is either hydrogen or a hydrocarbon group free of aliphatic unsaturation and containing from one to eight carbon atoms, and (c) an anhydrous solvent for components (a) and (b) which solvent molecules do not contain Zerewitinoff hydrogen.

2. A composition as defined in claim I wherein component (a) is one in which each of R, R, and R is a hydrocarbon group free of aliphatic unsaturation and has from one to eight carbon atoms, R' is wherein each of R' and R and R is as defined above, component (b) has the formula I in which R, R and R are as defined above, R is hydrogen, and R is a hydrocarbon radical which is free of aliphatic unsaturation and contains from 1 to 8 carbon atoms.

5. A composition as defined in claim 4 wherein component (a) is trimethylsilyl 3-acetoxymethyl-7-(N-trirnethylsilylamino)-A"-cephem-4-carboxylate, component (b) is N- trimethylsilylacetamide, and component (c) is acetonitrile.

I t i i 

2. A composition as defined in claim 1 wherein component (a) is one in which each of R1, R2, and R3 is a hydrocarbon group free of aliphatic unsaturation and has from one to eight carbon atoms, R10 is wherein each of R1, R2, and R3 are as defined above, component (b) has the formula V; and component (c) is an alkanonitrile having from 2 to 6 carbon atoms;
 3. A composition as defined in claim 2 wherein component (a) is trimethylsilyl 3-acetoxymethyl-7-(N-trimethylsilylamino)- Delta 3-cephem-4-carboxylate, component (b) is N,O-bis (trimethylsilyl)acetamide, and component (c) is acetonitrile.
 4. A composition as defined in claim 1 wherein component (a) is one in which each of R1, R2, and R3 is a hydrocarbon group free of aliphatic unsaturation and has from one to eight carbon atoms, R10 is wherein each of R1 and R2 and R3 is as defined above, component (b) has the formula I in which R1, R2, and R3 are as defined above, R4 is hydrogen, and R3 is a hydrocarbon radical which is free of aliphatic unsaturation and contains from 1 to 8 carbon atoms.
 5. A composition as defined in claim 4 wherein component (a) is trimethylsilyl 3-acetoxymethyl-7-(N-trimethylsilylamino)- Delta 3-cephem-4-carboxylate, component (b) is N-trimethylsilylacetamide, and component (c) is acetonitrile. 